Details

Autor(en) / Beteiligte

• Kaczor, Agnieszka A
• Silva, Andrea G
• Loza, Maria I
• Kolb, Peter
• Castro, Marian
• Poso, Antti

Titel

Structure-Based Virtual Screening for Dopamine D sub(2) Receptor Ligands as Potential Antipsychotics

Ist Teil von

• ChemMedChem, 2016-04, Vol.11 (7), p.718-729

Erscheinungsjahr

2016

Quelle

Wiley Online Library Journals【Remote access available】

Beschreibungen/Notizen

• Structure-based virtual screening using a D sub(2) receptor homology model was performed to identify dopamine D sub(2) receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D sub(2) ligands were identified (47.6% success rate, among them D sub(2) receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT sub(2A) receptors. The affinity (K sub(i) values) of the compounds ranged from 58nm to about 24 mu m. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D sub(2) receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D sub(2) pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D sub(2) receptor over the D sub(3) receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction. Potential antipsychotics: Novel dopamine D sub(2) receptor ligands were identified by using structure-based virtual screening. These compounds exhibited additional affinity for the 5-HT sub(1A) and 5-HT sub(2A) receptors, which is characteristic for second-generation antipsychotics. Importantly, one of the most active compounds is an orthosteric dopamine D sub(2) receptor ligand that lacks a protonatable nitrogen atom, which is a key element of the classical pharmacophore model.